Journal
SCIENCE
Volume 362, Issue 6414, Pages 557-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aat8407
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Funding
- NIH/NINDS [P50NS38377, R37NS067525, NS082205, U01NS082133, U01NS097049]
- JPB Foundation
- Jane and Lee Seidman Fund
- [U01 NS100610]
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The pathologic accumulation and aggregation of alpha-synuclein (alpha-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic alpha-syn causes neurodegeneration in PD are not known. Here, we found that pathologic alpha-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic alpha-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic alpha-syn toxicity. In a feed-forward loop, PAR converted pathologic alpha-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.
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